The role of cellular senescence in bone loss and recovery in periodontal disease

项目摘要/摘要 由牙周病(PD)导致的支持牙齿的牙槽骨丢失的患病率在第三季度急剧上升 以及40年的生命。因此，帕金森病是成年人牙齿脱落的主要原因。增长背后的机制 成年期帕金森病患者骨丢失的易感性尚不清楚。17%至23%的帕金森病患者对电流无反应 治疗，从而导致牙齿脱落。我们的长期目标是确定与年龄相关的骨骼的机制。 帕金森病的骨丢失，以开发基于机制的帕金森病骨丢失的治疗方法。发展中的一个潜在因素 帕金森病骨质流失的主要原因是衰老细胞的堆积。衰老细胞在组织中的积累越来越多 被认为是年龄相关疾病的驱动因素。为了减轻有害影响，衰老的细胞可以 被称为感觉剂的药物去除，这种药物选择性地诱导衰老细胞的凋亡。Fisetin是一种最近的 具有无明显不良反应的抗感觉剂的特点，正在进行靶向临床试验 以衰老的细胞负担为特征的病理状态。 我们使用结扎诱导PD(LIP)模型的初步研究表明，LIP诱导最初的快速 在幼鼠的第14天(2.5个月)，骨吸收随后由于骨形成而迅速恢复。在……里面 相比之下，成年小鼠在第14天(8-12个月)仍有显著的骨丢失。此外，成熟的小鼠也表现出 与幼鼠相比，骨体积丢失更大，表明对嘴唇诱导骨的易感性增加 在成熟小鼠中丢失。此外，成年唇裂小鼠的骨形成率低于年轻小鼠， 提示骨形成率降低是唇癌易感性增加的原因。 成年小鼠的骨丢失。我们发现衰老标记基因在牙周组织中的表达水平增加 成熟小鼠在帕金森病诱导前的组织中，提示衰老细胞在组织中积聚 增加成年小鼠对嘴唇引起的骨丢失的敏感性。我们的假设是 衰老的细胞是抑制骨恢复和增加骨丢失的关键因素。 帕金森病患者骨丢失的病理易感性，溶血治疗将改善帕金森病驱动的骨 损失。在这里，我们提出了以下目标：具体目标1：确定是否清除了预先存在的 衰老细胞所受的松果体素，可防止帕金森病患者牙槽骨丢失。12个月大的小鼠将会被 在诱导唇部之前，使用非瑟丁清除和防止年龄相关性衰老堆积，我们将 分析鱼腥草素对唇源性骨丢失的细胞清除作用。特定目标 2：确定非瑟素治疗是否能从帕金森病所致的骨丢失中恢复。我们将在12分钟内诱导LIP- 几个月大的小鼠，等到骨吸收进展到可以检测到的水平后，再开始非瑟素治疗。 然后我们将分析由LIP引起的骨丢失。我们的团队非常适合进行这些实验 在牙周学、骨生物学和肌肉骨骼组织细胞衰老方面的专业知识。结果来自 这项工作将引导我们进一步从机制上研究衰老在帕金森病中的作用，以实现我们的长期目标。

Project Summary/Abstract The prevalence of tooth-supporting alveolar bone loss by periodontal disease (PD) steeply rises in the 3rd and 4th decades of life. As such, PD is a leading cause of tooth loss in adults. Mechanisms behind the increased susceptibility to PD bone loss in adulthood are unknown. 17 to 23% of PD patients do not respond to current treatment and thus progress to tooth loss. Our long-term goal is to identify the mechanism of age-related bone loss in PD to develop mechanistically based therapies of PD bone loss. A potential factor in the development of PD bone loss is the accumulation of senescent cells. Senescent cell accumulation in tissues is increasingly recognized as a driver of age-associated disorders. To mitigate the deleterious effects, senescent cells can be removed by drugs called senolytics that selectively induce apoptosis in senescent cells. Fisetin is a recently characterized senolytic without observable adverse effects and is being evaluated in clinical trials targeting pathological conditions hallmarked by senescent cell burden. Our preliminary studies using the ligature-induced PD (LIP) model showed that LIP induces initial rapid bone resorption followed by a rapid recovery due to bone formation by day 14 in young mice (2.5 months). In contrast, significant bone loss remained at day 14 in mature mice (8-12 months). Also, mature mice showed greater bone volume loss compared to young mice, indicating the increased susceptibility to LIP-induced bone loss in mature mice. Furthermore, bone formation rate in mature mice with LIP was lower than young mice, suggesting that diminished bone formation rate is responsible for the increased susceptibility to LIP-induced bone loss in mature mice. We found increases in expression levels of senescence marker genes in periodontal tissue of mature mice before PD induction, suggesting that accumulation of senescent cells in the tissue increase the susceptibility to LIP-induced bone loss in mature mice. Our hypothesis is that accumulation of the senescent cells is a critical factor responsible for inhibiting bone recovery and for increasing bone loss susceptibility in the pathology of PD bone loss, and that senolytic treatment will improves the PD-driven bone loss. Here, we propose the following aims: Specific Aim 1: Determine if the clearance of pre-existing senescent cells by the senolytic, fisetin, will prevent PD alveolar bone loss. 12-month-old mice will be pre- treated with fisetin to clear and prevent age-related senescent accumulation before inducing LIP, and we will analyze the effect of senescent cell clearance by fisetin pre-treatment on LIP-induced bone loss. Specific Aim 2: Determine if fisetin treatment will induce recovery from PD-induced bone loss. We will induce LIP in 12- months-old mice and wait until bone resorption progress to detectable levels before starting fisetin treatment. We will then analyze bone loss induced by LIP. Our team is uniquely suited to conduct these experiments with expertise in periodontology, bone biology, and cellular senescence in musculoskeletal tissue. Outcomes from this work will lead us to further mechanistic studies of the role of senescence in PD toward our long-term goal.